This invention is directed to compounds having antibacterial activity, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis and treatment of bacterial infections using the compounds.
Because the effectiveness of many drugs currently available for prophylaxis and treatment of bacterial infections is being compromised by the emergence of drug-resistant bacteria, the introduction of novel antibacterials would be beneficial for their therapeutic value and their contribution to the antibacterial arts.
Accordingly, the first embodiment of this invention is directed to compounds, and salts, prodrugs, and salts of prodrugs thereof, which are useful as antibacterials, the compounds having formula (I) 
in which
one of A1 or R4 is OH or OR11 and the other is C(O)OH or C(O)OR60;
R1 and R2 are hydrogen or taken together are xe2x95x90O;
R3 is hydrogen, C(CH3)3, Oxe2x80x94CH2CHxe2x95x90CH2, or methyl substituted with 2,4-dimethoxyphenyl;
R5 is hydrogen, alkyl, halo, OH, CF3, CH2CF3, CF2CF3, or OR11;
R6 is hydrogen, halogen, alkyl, CN, NO2, C(O)H, Cxe2x89xa1CH, Cxe2x89xa1C(alkyl), Cxe2x89xa1CCCl3, Cxe2x89xa1CCF3, CHxe2x95x90CH2, or OR11;
R7 is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, NH(R12), or N(R13) (R14);
R11 is alkyl, C(O)R70, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, xe2x80x94NH2, xe2x80x94NH(alkyl), and xe2x80x94N(alkyl)2;
R12, R13, and R14 are independently alkyl or alkyl substituted with a substituent selected from the group consisting of heterocyclyl, xe2x80x94NH2, xe2x80x94NH(alkyl), and xe2x80x94N(alkyl)2; and
R60 and R70 are independently alkyl, aryl, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, xe2x80x94NH2, xe2x80x94NH(alkyl), and xe2x80x94N(alkyl)2;
in which, for the foregoing,
each aryl, heteroaryl, heterocyclyl, and bicyclic heterocyclyl is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of alkyl, halo, xe2x80x94CN, xe2x80x94OH, xe2x95x90O, xe2x80x94CF3, xe2x80x94OR30, xe2x80x94C(O)R35, xe2x80x94C(O)OH, xe2x80x94C(O)OR35, xe2x80x94NH2, xe2x80x94NH(R35), xe2x80x94N(R35) (R36), xe2x80x94C(O)NH2, xe2x80x94C(O)NH(R35), and xe2x80x94C(O)N(R35)(R36);
in which
R30 is alkyl or alkyl substituted with a substituent selected from the group consisting of halo and xe2x80x94OR45;
R35 and R36 are independently alkyl or alkyl substituted with phenyl; and
R45 is alkyl.
A second embodiment is directed to a process for making the compounds of the invention.
A third embodiment is directed to intermediates which are useful in the second embodiment.
A fourth embodiment is directed to compositions for the prophylaxis and treatment of bacterial infections in a fish or a mammal comprising the compounds of the invention and an excipient.
In a preferred fourth embodiment, the bacterial infection is quinoline-resistant bacterial infection.
A fifth embodiment is directed to a method for prophylaxis and treatment of bacterial infection in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound of the first embodiment.
In a more preferred fifth embodiment, the bacterial infection is quinolone-resistant bacterial infection.
A sixth embodiment of this invention is directed to a method for inhibiting bacterial protein synthesis in a fish or a mammal comprising administering thereto a therapeutically effective amount of a compound, or salt, prodrug, or salt of prodrug thereof, having formula (I) 
in which
one of A1 or R4 is OH or OR11 and the other is C(O)OH or C(O)OR60;
R1 and R2 are hydrogen or taken together are xe2x95x90O;
R3 is hydrogen, C(CH3)3, Oxe2x80x94CH2CHxe2x95x90CH2, or methyl substituted with 2,4-dimethoxyphenyl;
R5 is hydrogen, alkyl, halo, OH, CF3, CH2CF3, CF2CF3, or OR11;
R6 is hydrogen, halogen, alkyl, CN, NO2, C(O)H, Cxe2x89xa1CH, Cxe2x89xa1C(alkyl), Cxe2x89xa1CCCl3, Cxe2x89xa1CCF3, CHxe2x95x90CH2, or OR11;
R7 is halo, aryl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, NH(R12), or N(R13)(R14);
R11 is alkyl, C(O)R70, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, xe2x80x94NH2, xe2x80x94NH(alkyl), and xe2x80x94N(alkyl)2;
R12, R13, and R14 are independently alkyl or alkyl substituted with a substituent selected from the group consisting of heterocyclyl, xe2x80x94NH2, xe2x80x94NH(alkyl), and xe2x80x94N(alkyl)2; and
R60 and R70 are independently alkyl, aryl, or alkyl substituted with a substituent selected from the group consisting of halo, aryl, xe2x80x94NH2, xe2x80x94NH(alkyl), and xe2x80x94N(alkyl)2;
in which, for the foregoing,
each aryl, heteroaryl, heterocyclyl, and bicyclic heterocyclyl is unsubstituted or subatotuted with one, two, or three substituents independently selected from the group consisting of alkyl, halo, xe2x80x94CN, xe2x80x94OH, xe2x95x90O, xe2x80x94CF3, xe2x80x94OR30, xe2x80x94C(O)R35, xe2x80x94C(O)OH, xe2x80x94C(O)OR35, xe2x80x94NH2, xe2x80x94NH(R35), xe2x80x94N(R35) (R36), xe2x80x94C(O)NH2, xe2x80x94C(O)NH(R35), and xe2x80x94C(O)N(R35)(R36), in which
R30 is alkyl or alkyl substituted with a substituent selected from the group consisting of halo and xe2x80x94OR45;
R35 and R36 are independently alkyl or alkyl substituted with phenyl; and
R45 is alkyl.